Field of Invention
The instant disclosure relates to a method of preparing drug. More particularly, the instant disclosure relates a method of preparing drug agglomerate.
Description of Related Art
In the pharmaceutical industry, particle characterization of powder materials has become one of the crucial aspects in drug product development and it should be critically controlled within the formulating processes especially for solid oral dosage forms. The size distribution and shape of the particles can affect bulk properties and processability, thus during the formulating processes such as blending, tabletting and pellet coating it is required to have the particles in similar size at first. In addition, the particle size distribution of the drug substance may also have significant effects on final drug product performance (e.g., dissolution, bioavailability, content uniformity, stability, etc.)
The problems result from poor particle characterization can be solved by granulation. Granulation is a method to obtain larger particles in homogenized size distribution that can be used to facilitate formulation. In the practice, two types of granulation technologies are employed, namely, wet granulation and dry granulation. In wet granulation, granules are formed by the addition of a granulation liquid onto a powder bed which is under the influence of an impeller (in a high shear granulator or a twin screw granulator) or air (in a fluidized bed granulator). The agitation resulting in the system along with the wetting of the components within the formulation results in the aggregation of the primary powder particles to produce wet granules. The granulation liquid contains solvent which must be volatile so that it can be removed by drying. Conventional liquid include water, ethanol and isopropanol either alone or in combination. The dry granulation process is used to form granules without using a liquid solution because the product granulated may be sensitive to moisture and heat. Forming granules without moisture requires compacting and densifying the powders. In this process the primary powder particles are aggregated under high pressure. Either a large tablet (known as a “slug”) is produced in a complicate tablet press or the powder is squeezed between two rollers to produce a sheet of material (roller compactor). In both cases these intermediate products are then broken and sieved to desired size. However, if the drug is physical or chemical unstable, these techniques should not be adopted because the moisture and heat may accelerate the degradation of drug (in wet granulation) or the high compression pressure may force the drug to degradation (in dry granulation). By the way, theses granulation methods both need special equipment.
A fixed size drug loaded bead is another way to control the particle size. It is achieved by spraying a drug contained solution/suspension onto fixed size inert beads in a fluidized bed or in a centrifugal-fluid type granulator. However, it usually takes a prolonged time to load the drug onto the beads, especially for a large dosing quantity. Further, it also takes longer to apply a release rate controlling layer over such drug loaded bead.
In addition to the abovementioned methods, modifying the particle characterization of raw materials at source is another way to improve or provide additional functionality of excipients. Several pharmaceutical excipient suppliers can provide different grades of product that are suitable for various purposes. However, regarding to the drug substance, the choice is limited. That may be due to the inherent property of the drug substances or other cost considerations.
Spherical crystallization is a process of obtaining larger particles in spherical shape, by which crystallization and agglomeration can be carried out simultaneously and which can be utilized for improvement of flowability and compatibility of crystalline drugs (Powder Technol. 130, 2003, 298-306). Depending on the target particle characteristics, different techniques have been used for producing spherical crystals, for example, spherical agglomeration, ammonia diffusion method, emulsion solvent diffusion and neutralization method.
In 1974, Kawashima and Capes introduced the concept of obtaining larger particles by agglomeration during the crystallization step. Silica sand is dispersed in agitated carbon tetrachloride and agglomerated with calcium chloride aqueous solution. This process was used as a model system (Powder Technol. 10, 1974, 85-92). Later, Kawashima further disclosed a method to obtain a size enlargement of particles during the crystallization step by controlling crystal agglomeration with controlled properties (Science 4 Jun. 1982, 1127-1128). His method employed three solvents: one was the drug dissolution medium, i.e., good solvent; another was a medium which partially dissolves the drug and is moist, i.e., bridging liquid; and the last one was immiscible with the drug substance, i.e., poor solvent. The drug particles were first dissolved in good solvent, followed by re-crystallization when poured into poor solvent, and then agglomeration after bridging liquid was added. However, it is difficult to fully control the crystal property of the drug during dissolution-recrystallization procedure because the drug may not form an ideal shape or a desirable size which highly depends on drug nature and process parameters. In addition, whether the spherical agglomerates disclosed in those previous studies can be coated under pharmaceutical mass scale is uncertain.